BDR Thyroid

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Published2003Wiley-Liss, Inc. BirthDefectsResearch(PartB)68:479491(2003)

RoleofThyroidHormones inHumanandLaboratoryAnimal

Reproductive

Health

NeepaY.Choksi,1GloriaD.Jahnke,2CathySt.Hilaire,3andMichaelShelby1n

1NationalInstituteofEnvironmentalHealthSciences,ResearchTrianglePark,NorthCarolina2SciencesInternational,Inc.,ResearchTrianglePark,NorthCarolina

3SciencesInternational,Inc.,Alexandria,Virginia

The highly conserved nature of the thyroid gland and the thyroid system among mammalian species suggests it iscritical to species survival. Studies show the thyroid system plays a critical role in the development of several organsystems, including the reproductive tract. Despite its highly conserved nature, the thyroid system can have widelydifferenteffectsonreproductionandreproductivetractdevelopmentindifferentspecies.Thepresentreviewfocusesonassessingtheroleofthyroidhormonesinhumanreproductionandreproductivetractdevelopmentandcomparingittotheroleof thyroidhormones in laboratoryanimalreproductionandreproductivetractdevelopment.Thereviewalsoassessestheeffectsofthyroiddysfunctiononreproductivetractdevelopmentandfunction inhumansand laboratoryanimals.Considerationofsuchinformationisimportantindesigning,conducting,andinterpretingstudiestoassessthepotentialeffectsofthyroidtoxicantsonreproductionanddevelopment.BirthDefectsResB68:479491,2003. Published2003WileyLiss,Inc.w

Key words: thyroid hormones; animal; human; review; reproductivehealth; reproduction; reproductive tract; development; thyroid gland;fertility;rat;comparativephysiology

INTRODUCTIONThethyroidglandandthyroidhormonesarecentralto

human development. Animal and human studies in-dicate thyroid hormones play a role in cardiovascular,nervous, immune, and reproductive system develop-mentandfunction(Janninietal.,1995;Metzetal.,1996;Krassas, 2000). Specifically, numerous studies andreviews have evaluated the effect of thyroid hormoneson proper development and function of human repro-ductive tracts (Jannini et al., 1995; Krassas, 2000).Additionally, numerous studies have focused onevaluatingtheroleofthyroidhormonesonreproductivetract development in rodent models. However, there islimited information available in the current literaturediscussing the comparative reproduction physiology ofhumans and laboratory animals and the role of thyroidhormones in reproduction and reproductive tractdevelopment among species. The present review willdiscuss (1) similarities and differences in thyroid glandfunction and the role of thyroid hormones in humansandlaboratoryanimals,(2)theroleofthyroidhormonesin normal reproductive tract development and functioninhumansandlaboratoryanimals,and(3)theeffectsofthyroidhormonedysfunctioninhumansandlaboratoryanimalsonreproductivetractdevelopmentandfunction.Consideration of such information is important indesigning,conducting,andinterpretingstudiestoassessthepotentialeffectsofthyroidtoxicantsonreproductionanddevelopment.

NORMALTHYROIDGLANDFUNCTIONGeneral

Locatedintheneck,justbelowthelarynx,thethyroid

gland in humans is abrownishred organ having twolobes connected by an isthmus and consists of lowcuboidal epithelial cells arranged to form small sacsknownas follicles. The two principle thyroidhormonesare thyroxine (T4 or L3,5,30,50tetraiodothyronine) andtriiodothyronine (T3 or L3,5,30triiodothyronine). Thesehormones are composed of two tyrosyl residues linkedthrough an ether linkage and substituted with four orthree iodineresidues,respectively.T3 isthebiologicallyAbbreviations: FSH, follicle stimulating hormone; GD, gestation day;GnRH, gonadotropinreleasing hormone; GTT, gestational transientthyrotoxicosis; hCG, human chorionic gonadotropin;HPT, hypothala-micpituitarythyroid;

IGF1,

insulinlike

growth

factor1;

Km,

MichaelisMentonconstant;LH, leuteinizinghormone;rT3,reverseT3;SHBG,sex

hormone binding globulin; T3, triiodothyronine or L3,5,30triiodothyr-onine; T4, thyroxine or L3,5,30 ,50tetraiodothyronine; TBG, thyroxine-binding globulin; TBPA, thyroidbinding prealbumin; TPO, thyroidperoxidase;TR,thyroidreceptor;TRH,thyrotrophinreleasinghormone;TSH,thyroidstimulatinghormone;TTR,transthyretin;UDPGTs,uridinediphosphataseglucuronosyltransferases.Grantsponsor:NIEHS;Grantsponsor:SciencesInternational,Inc.;Grantnumber:N01ES85425.nCorrespondence to: Michael Shelby, Ph.D., National Institute ofEnvironmental Health Sciences, PO Box 12233, MD EC32, ResearchTrianglePark,NC27709.Email:[email protected];Accepted10September2003PublishedonlineinWileyInterScience(www.interscience.wiley.com)DOI:10.1002/bdrb.10045

wThisarticle isaUSGovernmentworkand,assuch,isinthepublicdomainintheUnitedStatesofAmerica.
mailto:[email protected]:[email protected]:///reader/full/www.interscience.wiley.commailto:[email protected]:///reader/full/www.interscience.wiley.com


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480 CHOKSIETAL.activehormoneandT4,themajorthyroidhormonethatis secreted from the thyroid gland, is considered aprecursororprohormone.DeiodinationofT4inperiph-eraltissues(e.g.,liver) leadstoproductionofT3(whichhastwoiodinesontheinnerringandoneiodineontheouter ring of the molecule) and reverse T3 (rT3; whichhasoneiodineontheinnerringandtwo iodinesontheouterringofthemolecule);rT3hasnoknownbiologicalactivity(Fig.1).Thegrossstructureofthethyroidgland in laboratoryanimals,twolobesconnectedbyanisthmus,issimilartothatdescribedforhumans.However,therearemorpho-logical differences in the follicles. Compared to thefollicles in primates, which are large with abundantcolloid and follicular cells that are relatively flattened(low cuboidal), rodent follicles are relatively small andoften surrounded by cuboidal epithelium (U.S. EPA,1998).It isproposedthatthemorphologicaldifferences,in part, are due to differences in thyroid hormoneturnover (seebelow). The structures of T3 and T4 arethesamein laboratoryanimalsandhumans.

The pattern of thyroid development among rodents,sheep, and humans is similar. However, the timingof various perinatal developmental events differsamongspecies.Ratsarebornrelativelyimmature.Thus,latedevelopmentaleventsthatoccurinuteroinhumansoccur postnatally in rats. Thyroid development insheep, comparatively, appears to occur mostly in utero.The developmental life stage at which thyroid receptor(TR) binding first occurs is one example of the

NH2

C COOHI CH2

H

HO

Monoiodotyrosine (MIT)

I

I O

NH2

HO CH2 C COOHI

HI

3,5,3',5'-Tetraiodothyronine (L-thyroxine) (T4)

I

I O

NH2

HO CH2 C COOH

H

differences among species in thyroid development.TR binding occurs mid to lategestation (averagegestationis3weeks)inrats,duringthelattertwothirdsof gestation (average gestation is 20.5 weeks) insheep,andbetweengestationalweeks10and16(averagegestation is 39 weeks) in humans (Fisher and Brown,2000).

ThyroidHormoneSynthesis,Secretion,andTransport

Thyroidgland folliclesplayacriticalrole incompart-mentalizing the necessary components for thyroidhormone synthesis. Thyroglobulin, a glycoprotein thatcomprises134tyrosineresiduesandisoneofthestartingmolecules for thyroid hormone synthesis, fills thefollicles. Epithelial cells of the thyroid gland have asodiumiodide symporter on thebasement membranesthat concentrates circulating iodide from the blood.Once inside thecell, iodide is transported to the folliclelumen.Thyroidperoxidase(TPO),anintegralmembraneprotein present in the apical plasma membraneof thyroid epithelial cells, catalyzes sequential reactionsin the formation of thyroid hormones. TPO firstoxidizes iodide to iodine, then iodinates tyrosines onthyroglobulintoproducemonoiodotyrosineanddiiodo-tyrosine. TPO finally links two tyrosines to produce T3and/orT4.

In rodents and humans, the peptide linkagebetweenthyroid hormones and thyroglobulin is enzymatically

NH2

I CH2 C COOH

H

HO

I

Diiodotyrosine (DIT)

I

I O

NH2

HO C COOH

H

I CH2

3,5,3'-Triiodothyronine (T3)

I

I O

NH2

HO CH2 C COOH

HI

3,3'-Diiodothyronine 3,3',5'-Triiodothyronine (Reverse-T3)

Fig.1.Structuralformulasofthyroidhormonesandrelatedcompounds.BirthDefectsResearch(PartB)68:479491,2003


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481THYROIDHORMONESANDREPRODUCTIVEHEALTHcleaved. Thyroid hormonecontaining colloid then isinternalizedattheapicalsurfaceofthethyroidepithelialcellsby endocytosis. Lysosomes, which contain hydro-lytic enzymes, fusewith theendosomesandrelease thehormones. Free thyroid hormones diffuse into bloodwhere they reversibly complex with liverderivedbind-ingproteinsfortransporttoothertissues.

The chemical nature of these liverderived bindingproteinsandtheproportionofT3andT4bindingtotheseproteinsvaryconsiderablyamonganimalspecies.T3andT4, in different species, can reversibly bind to threedifferentliverderivedbindingproteins:thyroxinebindingglobulin (TBG), transthyretin (TTR; also called thyroid-

bindingprealbumin,TBPA),andalbumin(Robbins,2000).Lipoproteins alsobind a small fraction of the availablethyroidhormones.TBGisamonomerthatisamemberofthe serine protease inhibitor (serpin) superfamily ofproteins (Flink et al., 1986; Robbins, 2000). TTR is atetramer that iscomposed of four identicalsubunits thatareeachcomposedof127aminoacids(Poweretal.,2000).Albumin is a monomer that has substantial sequencehomology with afetoproteins and vitamin Dbindingproteins(Robbins,2000).Thereislittleoverallaminoacidsequencehomologybetweenthethreebindingproteins.

Innormalhumanplasma,theT4bindingdistributionis roughly 80%bound to TBG, 15% to TTR, and 5% toalbumin and lipoproteins. For T3, human plasma

binding distribution is 90% bound to TBG and theremainder to albumin and lipoproteins. T4 and T3

binding distribution correlates with affinity of thehormones for thebinding proteins; T4 and T3 affinityforTBGismuchhigherthantheiraffinitiesforalbuminorTTR(Kaneko,1989;Robbins,2000).

As noted above, thyroid hormones also interact withTBG, TTR, and albumin in rodents and other animals.There is moderate to high amino acid sequence homol-ogyoftheproteinsamongspecies(Imamuraetal.,1991;Tsykin and Schreiber, 1993; Power et al., 2000). Forexample, TTR sequence homology among humans andothermammals,birds,reptiles,and fishrangesfrom67to 92% (Power et al., 2000). Compared to humans,albumin appears to be the major binding protein inadultrodents.RodentscontainagenethatcanencodetheTBG protein,but it is expressed at very low levels inadultanimals(Vranckxetal.,1990;RouazeRometetal.,1992;Tanietal.,1994).DevelopmentalstudiesshowTBGproteinlevelsincreaseduringtheearlypostnatalperiodin rodents, but then decline to very low levels byweaning and remain low through the remainder of theanimalslifespan(Savuetal.,1987,1991;Vranckxetal.,1990).Asinhumans,T3andT4havehigheraffinityforTBG than TTR or albumin in rodents. However, sinceTBG is expressed at low levels, almost all T4 andT3bind to TTR and albumin in adult rodents (Keneko,1989).

Experimentalmanipulations(e.g., increases insamplevolume) have enabled the detection of TBG levels indifferent rodent species and have shown there aredifferences in TBG levels among different species ofadultrodents.TrendsinratTBGlevelsappeartocloselymimic those seen in humans, whereas trends in miceTBG levels appear to be opposite of what is seen inhumans. For example, TBG levels are higher in adultfemale rats and humans when compared to adult malerats and humans. In contrast, TBG levels are higher in

adult male mice when compared to adult female mice(Vranckx et al., 1990). Another example is seen whenevaluating TBG levels during pregnancy. TBG levelsincrease in humans and rats during pregnancy, whileTBG levels decrease in mice during pregnancy (Savuetal.,1989).Thebasisforthisobservedspeciesdifferenceduring pregnancy is unclear. However, steroidinducedalterationsinTBGsynthesisorclearanceareproposedtoplayarole.Thyroidstimulatinghormone(TSH),whichissecreted

by the anterior pituitary gland, regulates thyroidhormonesynthesisandsecretioninhumansandlabora-tory animals. Thyrotrophin releasing hormone (TRH) issecreted by the hypothalamus and regulates pituitaryTSH secretion. Control of circulating concentrations ofthyroidhormoneisregulatedbynegativefeedbackloopswithin the hypothalamicpituitarythyroid (HPT) axis(ScanlonandToft,2000).Ingeneral,bloodconcentrationsof thyroid hormones above normal levels inhibit thereleaseofTRHandTSH.Whenthyroidhormoneserumlevelsaredecreased,TRHandTSHreleaseisstimulated.Increased TSH levels are associated with increasedthyroid cell proliferation and stimulation of T3 and T4production(Fig.2).

PhysiologicalEffectsofThyroidHormonesThe mechanism of cellular T3 uptake is an area that

continuestobeunderstudy.CellularentryofT3througha carriermediated process is one proposed mechanismofaction(Hennemannetal.,2001).InvitrostudiesshowthepresenceofspecificT3andT4bindingsites/carriersin different laboratory animal and human tissues(Hennemann et al., 2001). An alternative mechanism ofcellulartransportisthepresenceofselectiveandspecificinteractionofthyroidhormonebindingproteinswithcellsurface receptors. Reports have noted the presence ofreceptorsforTBGandTTRonsomecells(Robbins,2000).The function of these receptors is unclear, but it isproposed they couldbe involved in targeting thyroidhormones to specific subcellular sites. Potential speciesand sex differences in cellular T3 uptake are currentlynotdefined.

Upon entry into the cell, T3 is transported to thenucleus for interaction with TR. Results of currentstudiessuggestacombinationofmechanisms(diffusion,cytosolic binding proteins, interaction with cytosolicreceptors)playaroleintransportingT3fromthecytosolto the nucleus. Species and sex differences in intracel-lular transport of T3 are not completely understoodcurrently.

TRfunctionashormoneactivatedtranscriptionfactorsandactbymodulatinggeneexpression.Similartoothernuclear receptors, the TR consists of a transactivationdomain, a DNAbinding domain, and a ligandbindingand dimerization domain (OShea and Williams, 2002).TRbindDNAintheabsenceofhormone,usuallyleadingto transcriptional repression. Hormonebinding is asso-ciatedwithaconformationalchangeinthereceptorthatleads to transcriptional activation. Mammalian TR (TRaand TRb) are encoded by two genes. The encodedmRNAsarealternativelysplicedtoproduceninemRNAisoforms (OShea and Williams, 2002). Studies indicatethat of the nine expressed TR in humans, only four

BirthDefectsResearch(PartB)68:479491,2003


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482 CHOKSIETAL.

Pituitary

Gland

Thyroid Gland

Blood

T3 and T4 free or bound to

TBG, Albumin, or

Transthyretin

T3 T4

Hypothalamus

Target Tissues

T4 T3

Deiodinase I or II

TSH

Liver

Elimination(gut)

Kidney

Elimination(urine)

T3/T4 Negative

Feedback

TRH

Fig.2.Thyroidsystemdiagram.

appear to bind to T3: TRa1, TRb1, TRb2, and TRb3(Harvey and Williams, 2002). Homologs to these recep-torsalsoappeartobeexpressedinrodents(OSheaandWilliams,2002).TRa2,whichisencodedbytheTRagene,fails tobind T3 and acts as a weak antagonist in vitro.TRa3,DTRa1,andDTRa2areencodedby theTRageneand act as dominant negative antagonists. TheDTRb3,encodedby the TRb gene, also lacks the DNAbindingdomainandisapotentrepressorinvitro.Thesereceptorsare developmentally regulated and are present incharacteristicconcentrationratiosinvariousadulttissues(Oppenheimer and Schwartz, 1997; Harvey andWilliams,2002).

The primary functions of T3 are to regulate carbohy-drateandproteinmetabolism inallcells.Thus,changesin T3 can affect all organ systems of the body withprofound effects on the cardiovascular, nervous, im-mune, and reproductive systems. In the developinganimal and human, the thyroid regulates growth andmetabolism and plays a critical role in tissue develop-

ment and differentiation. For example, T3 affectsperinatal development of aadrenergic receptors and isimportantforcardiacbadrenergicreceptordevelopment(Metzetal.,1996;Tan etal., 1997).T3also may interactwithandmodulatetheactionofotherhormonalsystemssuchasgrowthhormonesandsteroids.

MetabolismandExcretionofThyroidHormonesThyroid hormone activity canbe regulatedby three

separate enzymatic pathways: deiodination, glucuroni-dation, and sulfation. Deiodination in humans is typi-cally associated with production and metabolism of T3and plays a major role in metabolism of thyroidhormones.

Approximately80%oftheintracellularproductionandmetabolismofthyroidhormonesproceedsbysequentialenzymatic removalof iodine from the molecules (Kelly,2000). Type I and type II deiodinases, which removeiodinefromthe50 positiononthyroidhormones,convert



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483THYROIDHORMONESANDREPRODUCTIVEHEALTHTable1

PropertiesofDeiodinasesPresentinLaboratoryAnimalsandHumansProperty DeiodinaseTypeI DeiodinaseTypeII DeiodinaseTypeIII

(5and5deiodinaseactivity) (5deiodinaseactivity) (5deiodinaseactivity)LimitingKm 0.5mM 12nM 520mMReactioncatalyzed T4torT3orT3 T4toT3 T4torT3T3toT2Inhibitors

Thiouracils,

iopanoate,

Iopanoate,

flavonoids,

high

T4

levels,

rT3

Iopanoate,

flavonoids

halogenatedaromates,propranolol

Tissuedistribution Thyroid,kidney,liver,euthyroid CNS,pituitary,brownadiposetissue, Almostalltissuesexceptliver,pituitary,CNS,skeletalmuscle, placenta kidney,thyroid,pituitary;placenta highinratfetus

Hyperthyroidism Increase Decrease IncreaseHypothyroidism Decrease Increase Decrease

T4 to T3 in peripheral tissues. Type I deiodinases alsomay remove iodine substituents from the 5 position onthyroid hormones, which leads to the formation of rT3from T4. Approximately 85% of T3 in the blood isproducedbytheactionofTypeIdeiodinaseinavarietyoforgans(CrantzandLarsen,1980).TypeIIIdeiodinases,which remove iodine from the 5 position on thyroidhormones, catalyze the conversion of T4 and T3 to rT3and diiodothyronines (T2), respectively. T2 are in turndeiodinated to form monoiodothyronines. DeiodinaseenzymeactivitycanberegulatedbyT3andT4levelsandindependently of the other deiodinases. Additionalinformation on the deiodinases are found in Table 1(Kelly,2000;Kohrle,2000).

Thyroid hormones are glucuronidated primarily byuridine diphosphatase glucuronosyl transferases (UDPGTs) and excreted by the kidneys during Phase IImetabolism. Three UDPGTisoenzymes, whichbelongto the UGT1Agene subfamily, metabolize T3and T4 intherat.Types1and2glurcuronidateT4andrT3,whiletype 3 glucuronidates T3. Glucuronidation is a majorthyroid hormone metabolism pathway in laboratoryanimalsandstudies indicate that therearespecies andgenderdependent variations in enzyme activity (Kelly,2000).Glucuronidationnormallyisnotasignificantrouteof metabolism in humans,but maybecome importantwhenT3levelsareincreased(Findlayetal.,2000).UDPGTsbelongtotheUGT1AfamilyglucuronidaterT3andT4inhumans(Findlayetal.,2000).UDPGTactivitycan

be modulatedby numerous xenobiotics and the impactof longterm exposure to compounds that alter thyroidhormone glucuronidation pathways is currently un-known(Kelly,2000).

SulfationofT3facilitatesthemetabolismofT3bytypeIdeiodinaseenzymes;however,itisapoorlyunderstoodpathway of thyroid hormone metabolism. The sulfationpathway does not appear to contribute significantly tothyroidhormonemetabolisminhealthyhumans,buttherole of sulfation in thyroid hormone metabolism mayincrease when Type I deiodinase activity is decreased.Animal studies indicate that activation of the sulfationpathwayinhibitsT3formationandincreasesdegradationof T4 and rT3 to inactive metabolites (Kelly, 2000).However, T3sulfate activity may be important in thehuman fetus. It is proposed that, in the absence ofdeiodinationofT4,T3sulfateservesasasourceof fetal

T3,whereT3isformedbytissuesulfatasesandbacterialsulfatasesintheintestine(BruckerDavis,1998).

Thyroidhormonehalf-lifeandTSHlevels. Theserumhalflife ofT4andT3 innormalhumanadults is59 days and 1 day, respectively. Comparatively, theserumhalflifeofT4andT3inratsis0.51and0.25days,respectively. Thebasis for the difference in halflives isnot completely understood,but it is proposed that thelack of highaffinity T4binding proteins (e.g., TBG) inthe adult rat plays a role. The lack of highaffinity T4

bindingproteinsintheratisproposedtoleadtoahigherserumlevelofunboundT4,whichismoresusceptibletoremoval (e.g., metabolism, excretion; U.S. EPA, 1998).HigherproductionofratT3,duetotheshorthalflife,ispostulated tobe drivenby highbasal TSH levels. ThehigherproductionrateofTSH inrodentsisproposedtoplayaroleindifferencesinfolliclemorphologybetweenrodentsandhumans.StudiesbyDohleretal.(1979)alsosuggest

that

anumber

of

other

factors

can

contribute

to

and significantly alter the levels of and turnover of T3andT4inrats.

The basal level of TSH in rats is an area of someuncertainty. Several studies indicate thatbasal levels ofTSHrangefrom14ng/mL(Hiasaetal.,1987;McClain,1989; Vansell and Klaassen, 2001). However, othercitationsindicatethatbasalratTSHlevelsrangebetween50 and 200 ng/mL (U.S.EPA, 1998). It is proposed thattheseTSH levelsarehigherthanthoseseen inhumans.

In addition to species differences, sex differences inthethyroidhormonesystemexistinrats.TSHlevelsareapproximately the same in men and women,but adultmaleratshavehigherbasalTSHlevelsthanadultfemalerats. Additionally, the height of the thyroid follicles areapproximately

equivalent

in

both

human

sexes

but

are

often greater in adult male rats than adult female rats(Capen,1996).

ROLEOFTHETHYROIDHORMONESINREPRODUCTIONANDREPRODUCTIVE

TRACTDEVELOPMENTNormal function of the HPT axis is important in

laboratory animal and human reproduction and devel-opment in both sexes. Thyroid hormones effects onreproductivefunction,fertility,andfetaldevelopmentin



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484 CHOKSIETAL.humans have largely been identified through adverseoutcomesreportedforindividualswiththyroiddysfunc-tion and through experimental manipulation of thyroidhormonesinlaboratoryanimals.

ReproductiveEffectsinMalesHumans. Normal thyroid hormone levels are im-

portant

for

maturation

of

the

testes

in

prenatal,

early

postnatal,andprepubertalboys.Studiesindicatethatthemajor targets of T3binding in the testis are the Sertolicells.Thesecells,alongwiththegonocytes,comprisetheseminiferousepithelium of the testisandarecritical fornormal sperm maturation (Jannini et al., 1995). In vitrostudiessuggestthatT3activationofTRa1playsaroleintestes differentiation and development (Jannini et al.,2000). T3 has been shown to increase glucose carrierunits, insulinlike growth factor1 (IGF1), and inhibin;decrease aromatase activity and androgen bindingprotein; and inhibit the expression of Mullerianinhibit-ingsubstancebySertolicells(Jannini,etal.,1995).

Laboratory animals. T3 affects testis maturationin theratasdescribedabove forhumans.TRaandTRbare expressed in the testes of animals (Buzzard et al.,2000).It isproposedthatTRa1 isthespecificisoformofTRinvolvedintestisfunctionanddevelopment,andthemain targetofT3 istheSertolicell.MaximalSertolicellproliferation coincides with the maximal T3 bindingcapacityinthetestis.Additionally, T3playsasignificantrole in seminiferous epithelium differentiation (Janninietal.,1995).RodentstudiesalsohavedemonstratedthatT3 is important in the maturationof theLeydigcells intheinterstitiumofthetestis.T3isnecessarytoinitiatethedifferentiation of mesenchymal cells into Leydig pro-genitorcellsandworks in concertwithotherhormones(e.g.,leuteinizinghormone(LH),IGF1)inthepromotionof Leydig cell development (MendisHandagama andAriyarante,2001).

Data from deer, sheep, cattle, birds, and mink alsosuggest that T3 is a component of the neuroendocrinesystem regulating circannual (seasonal) cycles of repro-ductive activity in these species (Jannini et al., 1995).Although the mechanism is not known, it is postulatedthat T3 triggers cessation of reproduction at the end ofthe reproductive season since circulating T3 levels indeer rise at the time of seasonal transition to thenonbreeding state and thyroidectomy results in theabsenceoftheseasonalregressionofthetestis.

ReproductiveEffectsinFemalesHumans. The molecular mechanisms that affect

female reproduction (including estrogen and androgenmetabolism, sexual maturation, menstrual function,ovulation, fertility, and ability to deliver fullterminfants) involve T3induced modulation of hormone-induced transcription pathways and factors that affecthormonal status (Krassas, 2000). For example, T3stimulates the production of sex hormone bindingglobulin (SHBG), a serum steroidbinding protein thatcan bind circulating testosterone, dihydrotestosterone,andestradiol.Thisstimulationprovidesanetincreasein

bound, circulating steroids (Krassas, 2000). Studiesindicate that thyroid hormones have little to no effectonfemalereproductivetractdevelopment.

Numerousthyroidchangesoccurinthemotherduringpregnancy in response to the need to provide the fetuswith thyroid hormones until the fetal HPT system isfunctional. For example, maternal thyroid gland isenlarged and iodideuptake is increased (Verslootetal.,1997). Additionally, estrogen levels in pregnant womenstimulateexpressionofTBGinliverandinduceroughlya doubling in serum concentrations. The observed TBGincrease is concurrent with increases in total T3 and T4serum concentrations (Karabinas and Tolis, 1998). Thisincrease in TBG occurs during the first trimester andreachesamaximumatgestationalweeks2024(Karabi-nasandTolis,1998).Freethyroidhormonelevelsusuallyremain within the normal range in most women;however, free thyroid hormone levels may exceed therange during the first trimester due to the release ofhumanchorionicgonadotropin fromtheplacenta (hCG;seebelow).

Additional changesrelated to the thyroidsystemandthyroid hormone levels include decreased maternalserum iodide concentrations and increased T3sulfatesources. In pregnant women, serum concentrations ofiodide decrease due to increased renal clearance andtransfer of iodide and iodothyronines to the fetus(AboulKhair et al., 1964). Placental transfer of iodideand monodeiodination of iodothyronines within theplacenta provide iodide to the fetus especially as fetalthyroidhormoneproductionincreasesinthesecondhalfof gestation. Increased loss of iodide and subsequentTSH stimulation of the thyroid gland causes maternalthyroidvolumetoincrease1020%duringpregnancy.

FetalThyroidSystemDevelopmentThyroid system development in the human fetus can

be divided into three phases. Phase I, which includesinitial development of the hypothalamus, the pituitarygland,andthethyroidgland,occursbetweenembryonicday 10 and gestational week 11. Follicular maturationand accumulation of iodide occursby gestational week11 (Fisher and Klein, 1981; Gillam and Kopp, 2001). TRare detectable in thebrainby the 10th week of humangestation and the presence of thyroglobulin in the fetalthyroidandT4inthebrainisobservedbythe11thweekof human gestation (Gillam and Kopp, 2001). DuringPhase II (gestational weeks 1035), maturation of thethyroidsystem isevidentfromaprogressiveincreaseinfetalserumTBG,TSHsecretion,TRinthebrain,andT3levels (Fisher and Klein, 1981; Klein et al., 1982; Gillamand Kopp, 2001). Phase III takes place in the lasttrimester and postnatally. Maturation of HPT interac-tion and control characterizes this period of develop-ment.Bythe4thpostnatalweek,maturationoftheHPTsystemappearstobecomplete.

Development of the rat thyroid gland during preg-nancy, which is approximately 3 weeks long, occurs inapproximatelythesamephasesandorderasinhumans.TR are detectable by gestation day (GD) 14 andthyroglobulin is first detectedby GD 15 (PerezCastilloetal.,1985;Kawaoi,1987;Rodriguezetal.,1992;).Iodineuptake, TPO expression, TSH secretion, and thyroidhormonesynthesisarefirstnotedbyGD17(Kawoi,1987;Rodriguez et al., 1992). Unlike humans, rats arebornduring Phase II of maturation of the thyroid system.Therefore, maturation of HPT interaction and control



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485THYROIDHORMONESANDREPRODUCTIVEHEALTH(Phase III) occurs postnatally in theratand is complete

by4weeksofage.Despite similarities between species in the order of

thyroid development, there are some significant differ-ences.Thefactthatthyroidsystemmaturationappearstooccuratabout4weeksinbothspecies,differencesinthelifespan of humans (about 70 years) and rats (about2 years) show that thyroid maturation occurs muchearlier in overalldevelopmentof humans. Additionally,ratfetaldevelopmentissolelydependentuponmaternalthyroid hormones until approximately GD 18 (of anapproximately 21day gestational period; Phase II); hu-man fetal development is at least partially dependentupon maternal T3 until approximately 34 weeks gesta-tion (of an approximately 266day gestational period;PhaseIII;FisherandKlein,1981).

Laboratoryanimals. T3levelsaffectestrouscycleregulation, behavior, pregnancy maintenance, fetalgrowth, and lactation in laboratory animals. Mating

behavior(lordosis)stimulatedinovarectomizedrodentsbyestradioladministrationisinhibitedbyT3,suggestingthat T3 may exert an inhibitory influence on estrogen-mediatedreproductivebehavior(Vasudevanetal.,2002).In addition, the thyroid gland is necessary for thetransition to the anestrous state in some seasonally

breeding animals. For example, in ewes T3 needs tobepresent at the end of the breeding season to initiateanestrous. T3, however, does not play a role inmaintaininganestrousandthetimingofthesubsequent

breedingseason(Vasudevanetal.,2002).Asinhumans,pregnancy alters thyroid status rodents. Normalpregnancy results in a decrease in the total T4 and T3present in animals that has been correlated tothe decrease in free T4 levels seen in humans (Calvoet al., 1990). Also similar to humans, the thyroid glandenlarges during pregnancy. However, unlike humans,uptake of iodide decreases in pregnant rats and nochanges were found in urinary excretion of iodideduringthelastdaysofgestation(Feldman,1958;Verslootetal.,1997).

Role of the placenta. Studies show that thedeiodinases present in the human placenta rapidlymetabolize maternal T4 to T3 for useby the fetus witha significant amount of T4 still transferred to the fetus(ChanandKilby,2000).TheplacentaisfreelypermeabletoiodideandTRH,butnottoTSH.ItisproposedthatthematernalTRHprovided to the fetusmayhavearole inregulatingfetalthyroidfunctionbeforecompletematura-tionoftheHPTsystem.DataindicatethatTRisoformsare present in the placenta and expression of receptorproteins increases with fetalage (Chanand Kilby,2000;LeonardandKoehrle,2000).

Near the end of the first trimester in humans, thematernal serum concentration of hCG producedby theplacenta is sufficient to partially stimulate thematernalHPT axis activity by binding to the TSH receptor.Activation of the TSH receptor by hCG leads tostimulation of T4 production, decreases in serum levelsofTSH,andincreasesinfreelevelsofT4,aneffectthatisexacerbated if more than one fetus isbeing carried. Inapproximately 2% of these cases, the degree of TSHdepression and T4 stimulation may lead to gestationaltransient thyrotoxicosis (GTT) in the mother (Glinoer,1997,1998).In themajorityofpregnancies, thiseffect is

transient and the normalization of free T4 levelscorrelateswithdecreasedhCGlevels.Mostclinicalcasesof GTT are very mild, presenting with symptoms ofhyperthyroidism (e.g., weight loss, increased anxiety)andanincreaseinepisodesofmorningsickness.

THYROIDDYSFUNCTIONTherearethreecategoriesof thyroiddysfunction thathave been characterized in adult humans: subclinical

hypothyroidism, overt hypothyroidism, and hyperthyr-oidism. Subclinical hypothyroidism is defined as aslightly elevated TSH concentration and normal serumfreeT3andT4concentrationsassociatedwithfewornosymptoms (Ross, 2000). The prevalence of such mildhypothyroidism increases with age for both sexes.Although there canbe various causes of this condition,many subclinical hypothyroidism patients are positivefor TPO antibodies, which may lead to overt hypothyr-oidism.

Overthypothyroidismorunderactivethyroidglandisthe most common clinical disorder of thyroid function(BravermanandUtiger,2000). It isbestdefined ashighserum TSH concentration and a low free T4 serumconcentration. Insufficient iodine levels or low iodineintake are a major cause of overt hypothyroidism.However, in areas where iodine intake is adequate, themost common cause of hypothyroidism is Hashimotosthyroiditis, an autoimmune disease causedby autoanti-

bodiestoTPO.Otherautoimmunediseasesandradiationalso are causes of hypothyroidism. Overall, women aremore susceptible to autoimmune disease than men,suggesting they maybe more susceptible to the devel-opmentofhypothyroidism.

Hyperthyroidism (or thyrotoxicosis) is characterizedby an increase in serum T3 and T4 and a decrease inserumTSH.Themostcommoncauseofhyperthyroidismis Graves disease (production of antibodies to TSHreceptor).Intwostudies,thepeakagespecificincidenceofGravesdiseasewasbetween20and49butincidencehasbeen reported to increase with age, with the peakoccurring at 6069 years in a Swedish study (Berglundetal.,1990).

The following sections discuss the effects of thyroiddysfunction on reproduction and reproductive tractdevelopment inhumansandlaboratoryanimals.RoleofThyroidHormoneDysfunctiononMale

ReproductionandReproductiveTractDevelopment

Humans. Adulthypothyroidism isassociatedwitheffects on gonadotropin secretion and bioactivity, sexsteroid metabolism, and testicular function, resulting innormal or decreased serum levels of SHBG, low totalserumtestosteronelevels,andnormallevelsofestradiol.A hypergonadotropic state was observed in severehypothyroid (myxedematous) men, but normal anddecreased levels were also seen. In hypergonadotropicmen, thebiological/immunological LH ratio also wasincreased (Jannini et al., 1995). It was proposed thathypothyroidism can decrease ejaculation volume andspermprogressiveforwardmotility(Janninietal.,1995).

As seen with adult hypothyroidism, adult hyperthyroidism also effects gonadotropin secretion and



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486 CHOKSIETAL.bioactivity and testicular function. Adult hyperthyroid-ism is associated with increased SHBG, LH, and FSHresponses to gonadotropinreleasing hormone (GnRH).Male hyperthyroidism also is associated with breastdevelopment (gynecomastia; up to 85% incidence),which maybe due to an increased estrogen/androgenratio, increased conversion of androgen to estrogen,increased serum levels of SHBG, and increased totaltestosterone and/or progesterone levels (Jannini et al.,1995). Furthermore, hyperthyroid males may have alower than normal sperm count, with normal motility,andadecreasedlibido.

StudiesoftheeffectsofT3onadultmalefertilityhaveled to conflicting results, possibly due to small studysizes. In studies of hyperthyroid male adults withGravesdisease,disruptionofthehypothalamicpituitary(HP) gonadal axis resulted in significantly decreasedspermmotilityandnormalspermdensityandmorphol-ogy(HudsonandEdwards,1992);thefreetestosteronetofreeestradiolratiowasbelownormalvalues.Inanotherstudy using adult males with Graves disease, spermcountwasdecreased,butnotspermmotility(Abalovichetal.,1999).Krassasetal.(2002), inaprospectivestudyon23hyperthyroidadultmales,showedspermmotilitywas significantly decreased and decreased libido wasreported inapproximatelyonehalfthestudysubjects.

Perinataland/orprepubertalalterationsinthethyroidsystem are associated with altered development of themalereproductivesystem.Innormalchildren,increasesin LH serum levels are greater than FSH serum levels(Janninietal.,1995).Comparatively, boyswithhypothyr-oidism exhibit increases in FSH serum levels that aregreater than LH serum levels. Precocious sexual devel-opment, which is characterizedby enlargement of thetestes without virilization, has been associated withprepubertal thyroid failure (Jannini et al., 1995). Histo-pathologicalstudiesof thetestis inmaleswithjuvenile-onset hypothyroidism show fibrosis and hyalinization,fibroblastic proliferation, and peritubular interstitialfibrosis, with sparse numbers of Leydig cells in theinterstitialspace.

Laboratoryanimals. AlteredT3activityproducesunique effects in different laboratory animal species.Studies inmalemonkeysshowedthatadministrationofT4 increased SHBG concentration, increased peripheralaromatization of androstenedione, did not alter cortisolglobulin binding, and increased testosterone levels(Bourgetetal.,1987).

Inmaturemalerats,administrationofT4(producingahyperthyroidstate) led to decreased total lipids,choles-terol,andphospholipidsinthetestes;increasedamountsof testicular testosterone; and increased testicular pyr-uvatekinaseactivity(Longcope,2000a).Inanotherstudy,administrationofT4tointactadultmalerats(producinga hyperthyroid state) led to a decrease in LH and FSHlevels and an increase in testosterone levels (Schneideretal.,1979).Interestingly,decreasesinLHandFSHlevelsalso were observed in male rats that were thyro-parathyroidectomized (producing a hypothyroid state)andlevelsreturnedtocontrollevelsafteradministrationofT4(Brunietal.,1975).

In rats, hypothyroidism induced or occurring soonafterbirth is associated with a marked delay in sexualmaturation and development. Hypothyroidism begin-ning in the perinatal phase and continuing through the

prepubertalperiod leads toanarrestofsexualmaturityand absent libido and ejaculate (Longcope, 2000a).Transient hypothyroidism is associated with increasedtranscription of genes associated with rat Sertoli celldivision(Bunicketal.,1994).Astheseratsage,testissize,Sertolicellnumber,andspermproductionareincreased(Cooke,1991;Longcope,2000b).Therefore,perinatalandneonatal hypothyroidism appears to retard Sertoli celldifferentiation, increases the period of Sertoli cellproliferation, and increases spermatogenic efficiency(Kirbyetal.,1992).

Administration of slightly higher than physiologicallevels of T4 to male mice appears to induce sexualmaturation. Furthermore, T3 administration decreasesproliferation and stimulates differentiation and glucoseuptakeinSertolicellsfromimmaturerats.Paradoxically,higher doses of thyroid hormones result in decreasedweightsoftestesandseminalvesiclesinmiceandrabbits(Longcope,2000a).RoleofThyroidHormoneDysfunctiononFemale

ReproductionandReproductiveTractDevelopment

Humans. Hypothyroidism is associated with de-

creased rates of metabolic clearance of steroids andincreases in peripheral steroid aromatization in adultwomen. Thebinding activity of SHBG is decreased inhypothyroid women. This decreased SHBG activityincreases the unbound fractions of testosterone andestradiol present in the plasma and leads to increasedlevelsofthesesteroidsthatareavailableandfunctional.Hypothyroidism also is associated with oliogomenor-rhea, amenorrhea, polymenorrhea, and menorrhagia(Krassas,2000).

Severe hypothyroidism is associated with diminishedlibido and failure of ovulation, but ovulation andconception canoccur in the presence ofmildhypothyr-oidism. These pregnancies are often associated withspontaneousabortionsinthefirsttrimester,stillbirths,orprematurebirths. Thyroiditis, due to autoimmune dis-ease, is especially common in the postpartum period(Krassas,2000).Thesepatientsmayexperiencehypothyr-oidism, hyperthyroidism, or hyperthyroidism followed

byhypothyroidismwithin this time period.Whilemostpostpartum thyroiditis patients regain normal thyroidfunction, many women develop permanent hypothyr-oidism.Studiesalsohaveobservedthatpregnantwomenwithautoimmune thyroiddisease,whowerediagnosedwithsubclinicalhypothyroidism,wereobservedtohavea greater risk of miscarriage early in the pregnancy(Glinoeretal.,1994).

Studies indicate that hyperthyroidism also alters thesteroid system significantly. Hyperthyroidism is asso-ciated with increased mean plasma levels of estrogen,androstenedione,andtestosterone;increasedsynthesisofandrostenedioneandtestosterone;decreasedclearanceof17bestradiol; and increased metabolism of androstene-dione to estrone and testosterone to estradiol (Krassas,2000). Mean LH levels inboth phases of the menstrualcyclewerehigherinwomenwithhyperthyroidismthanineuthyroid women. Similar to men, hyperthyroidism isassociatedwithincreasedlevelsofSHBG.Epidemiological studies of hyperthyroid women show increased inci-dencesofoligomenorrheaoramenorrhea(Krassas,2000).



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487THYROIDHORMONESANDREPRODUCTIVEHEALTHStudiesontheeffectsofhypothyroidismonpostnatal

developmentofthereproductivesysteminfemaleshaveproducedconflictingresults.Hypothyroidismininfancycan lead to a delay in sexual maturity. Additionally, hypothyroidism in early puberty can delay onset ofpuberty followedby anovulatory cycles. On the otherhand,insomecases,hypothyroidismhasbeenassociatedwith precocious puberty and galactorrhea, which isproposed to be due to overlapping actions of TSH,prolactin, FSH, and LH. Fetal hypothyroidism does notappear to affect female reproductive tract development(Krassas,2000).

Resultsofstudiesontheeffectsofhyperthyroidismonpostnatal development of the reproductive system infemalesalsoareinconsistent.Somestudies indicatethathyperthyroidism occurring before puberty delays theonsetofmenses,whileotherstudiesshownosignificanteffect on menarche. As with hypothyroidism, fetalhyperthyroidismdoesnotappear toaffectreproductivetractdevelopment ingirls(Krassas,2000).

Laboratory animals. Hypothyroidism in adultrodents is associated with altered estrous cycles andleadstoenhancedresponsestohCG(withdevelopmentof large cystic ovaries but few corpora lutea) in rats.Hypothyroidism does not result in sterility, but doesinterfere with gestation, usually during the first half ofpregnancy. Increased resorption of embryos, reducedlitter sizes, and increased stillbirths are noted in thesestudies.Adecreaseinuterineresponsetoestrogenalsoisnotedinhypothyroidrats(Longcope,2000a).

Hyperthyroidism in adult female rats, induced byadministration of T4, is associated with long periods ofdiestrus with few mature follicles or corpora lutea. Inrats,administrationofexcessT4hasbeenassociatedwithanincreaseornochangeinpituitaryLHandadecreasein serum LH. Furthermore, studies have shown that amarkedexcessofthyroidhormonescausesabortionandneonataldeath(Longcope,2000b).

Fetalhypothyroidism in therat isassociatedwith thedevelopment of small ovaries that are deficient in lipidand cholesterol. Hypothyroidism in sexually immaturerats is associated with delayed vaginal opening andsexual maturation, smaller ovaries and follicles com-pared to untreated control animals, and underdevel-opeduteriandvaginas.Incontrast,fetalhypothyroidismin sheep does not affect female reproductive tractdevelopment(Longcope,2000b).

Studies on the effects of hyperthyroidism on femalereproductivetractdevelopmenthaveproduceddifferingresultsinmiceandrats.Smalldosesofthyroidhormonegiven to young female mice resulted in earlier vaginalopening and onset of the estrous cycle than in controls(Longcope,

2000a).

In

contrast,

large

doses

of

T4

given

to

neonatalratsdelayedbothvaginalopeningandonsetofthe estrous cycle. Methodological limitations in the ratstudies(inductionofhypothyroidismafterabriefperiodof hyperthyroidism) limit the usefulness of these studyresults(Schneideretal.,1979).

SUMMARYSimilaritiesandDifferencesinThyroidFunction

BetweenLaboratoryAnimalsandHumansThe thyroid system plays a critical role in the

developmentandmaintenanceofseveralsystemswithin

the mammalianbody including,but not limited to, thecardiovascular, nervous, and reproductive systems. Todate,manystudieshave focusedonunderstandingandevaluatingthephysiologicalandbiologicalrolesthyroidhormones have on these systems. The presence of ahighly conserved thyroid system in mammals indicatesthissystemplaysanintegralroleinanimaldevelopmentandsurvival.

There is a significant literature database focused onassessingtheroleandeffectsofthethyroidglandandT3on reproduction in humans and in laboratory animals.However, there is limited analysis and information onthecomparativephysiologyof the thyroidsystemsroleamong species. Understanding and evaluating thedifferences and similarities among species is necessaryto ensure appropriate and complete study design andinterpretation of results from laboratory animals, andextrapolationtopotentialhumanhealthrisks.Therefore,thepresentarticlefocusesonevaluatingthesesimilaritiesanddifferences.

Overall, studies indicate that the anatomy of thethyroid gland and the synthesis of thyroid hormonesare similar in laboratory animals and humans. Regula-torymechanismsthatmodulatethyroidhormonesynth-esisandrelease(HPTaxis)alsoappeartobeconservedin humans and rodents. The presence of such aconserved system and the fact that the amino acidsequencesofthethyroidhormonebindingproteinsshowa high degree of sequence homology (between 70 and90%)providefurtherevidencethatthethyroidsystemisimportant inhumansandanimals.

There are, however, significant differences betweenhuman and rodent thyroid hormone pharmacokinetics,associatedwithdifferencesinthyroidglandmorphology.The shorter halflife of T3 and T4 in rats is associatedwithincreasedproductionintherat,whencomparedtothehuman(U.S.EPA,1998)Althoughthereasonsforthisdifferencearenotunderstoodcompletely,itisproposedthatverylowlevelsofhighaffinityT4bindingintheratplayarole.Thehigher turnoverofT3andT4 intheratleadstohigherbasalTSH levelsinratswhencomparedtohumans.Thehigherrateofthyroidhormonemetabo-lism in rats, when compared to humans, also isassociatedwith differences in follicle morphology.Suchdifferences also may have implications for thyroidhormone effects in reproductive tract development andreproduction. For example, rats are more prone tothyroid hyperplasia and tumors than humans (evenunder conditions of thyroid dysfunction in humans).When such effects are observed in rodent toxicitystudies, very careful consideration shouldbe given tothis fact before assuming that similar exposures inhumans would lead to similar effects. However, itshouldbekeptinmindthatexposuretoachemicalthatinduceshyperplasiaortumorsinrodentsmightleadtoadifferentadversethyroideffectinhumans.

Other distinctions between humans and laboratoryanimals are the mechanisms of thyroid hormone meta-

bolism. Both species rely on hepatic deiodinases toconvert the prohormone T4 to the active hormone, T3.In humans, deiodinases also play a major role indeactivating T3. In contrast, removal of T3 from thecirculationbyglucuronidationandsulfationpathwaysisgreater in rats than in humans. Therefore, in order topredict human health outcomes, a comparison of the



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488 CHOKSIETAL.Table2

SelectedParametersofThyroidSysteminHumansandRats(AdaptedFromU.S.EPA,1998)Parameter Human Rat

HalflifeofT4 59days 0.51dayHalflifeofT3 1day 0.25dayThyroxinebindingglobulinlevels High VerylowAmount

of

T4

required

in

absence

of

functional

2.2

mg/kg

bw/day

20

mg/kg

bw/day

thyroidglandT4production(rate/kgbw) 1X 10XSexdifferenceinserumTSHlevels Nodifference Adultmaleshavehigherlevelsthanadult

femalesFollicularcellmorphology Lowcuboidal Cuboidal

Follicularheightisequalin Follicularheightinmalesisgreaterthaninmalesandfemales. females

Table3ComparisonofThyroidSystemDevelopment inHumanandRats

Parameter Human(birthatgestationalweek39) Rat(birthatgestationalday21)Thyroidglanddevelopment TRdetectableby10thweekofgestation TRdetectablebyGD14Thyroglobulindetectableby11thweekofgestation ThyroglobulindetectablebyGD15

Iodideuptakeby11thweekofgestation IodideuptakedetectedbyGD17TSHsecretiondetectedbetween18and20weeks TSHsecretingcellsappearbyGD17gestationT4detectableandfollicularmaturationby11thweek TPOandthyroidhormonesynthesisofgestation detectedbyGD17T3secretionincreasesbetween18and20weeksgestation

Maturationofpituitarythyroid Becomesfunctionallateinthe1standearly2nd Becomesfunctionalinlategestationandaxis trimester postnatally

HPTmaturation(completefunctionalinteraction) HPTmaturation(completefunctionoccursinlasttrimesterandpostnatally interaction)occurs

postnatallyMaturationappearscompleteby4thpostnatalweek Maturationappearscompleteby4th

postnatalweek

magnitudeofthyroiddysfunctionthatresultsinadverseeffects in various organs/tissues andbetween humansandrodents iswarranted.

In addition to species differences, there are sexdifferencesinthethyroidhormonesystems.AdultmaleratshavehigherbasalTSHlevelsthanadultfemalerats,whereasTSH levelsareapproximately thesame inmenand women. Studies also indicate the height of thethyroidfolliclesareoftengreaterinadultmaleratsthanadult female ratsbut are approximately equivalent in

bothhumansexes(Capen,1996).Table2showsselectedparametersinhumansandrats.

Furthermore, therearedifferences in changes inTBGlevels among rats, mice, and humans. As mentionedpreviously, TBG levels increase in humans and ratsduring pregnancy, while TBG levels decrease in miceduringpregnancy(Savuetal.,1989).

Thisanalysisshowstherearesignificantdifferencesinthe basic morphology and biological activity of thethyroidsystemsinhumanandlaboratoryanimals(morespecifically, rodents) tobe considered when evaluatinganimalstudiesandextrapolatingtheseresultstohumanhealth effects. Due to differences in thyroid hormonesynthesis,basal TSH levels, metabolism, differences in

alterations to binding proteins during pregnancy, andendpoint sensitivity, findings in rodents that thyroidhormone, TSH, or TRH levels are altered due toexposures to an environmental agent may not correlatetoanadverseeffect inhumans.

DifferencesinThyroidDevelopmentThepatternofthyroiddevelopmentinrodentsappears

tobe similar to the pattern in humans. In rodents andhumans, TR receptors are the first component of thethyroid system detected. Thyroglobulin and iodineuptake are then observed. Finally, TSH secretion issufficient tobe quantified. Further details of the timepoints when these components are observed can befoundinTable3.

Despitesimilaritiesintheorderoffetalthyroidsystemdevelopment,thenoteddifferencesshouldbeconsideredwhenextrapolatinglaboratoryanimaleffectstohumans.Forexample, the rat thyroid system is significantly lessmature than humans at birth and likely leads todifferences in responses to neonatal exposures in ratsand humans. This difference, as well as other potentialspecies differences, does not necessarily indicate that



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489THYROIDHORMONESANDREPRODUCTIVEHEALTHeffects in animals are irrelevant to humans. However,careandfurtherstudiesshouldbeundertakentoassurethattheeffectsseeninanimalsarerelatedtotherelevantdevelopmentalstagesinhumans.

Furthermore, differences in the life stage when thethyroid system fully matures is another factor thatshould be fully evaluated when attempting to relateadverseeffectsinlaboratoryanimalstothosethatmightoccur in humans. As noted above, the thyroid systemmaturesearlier,relativetobirth,inhumansthanitdoesin rodents. Therefore, compensatory mechanisms thatmaybeinplaceinhumanneonatesmaynotbeavailabletorodentsatanequivalentlifestage.

SimilaritiesandDifferencesintheRoleofThyroidHormonesonReproductionand

DevelopmentThyroid hormones play acentral role in the develop-

ment of several laboratory animal and human systems.Overall, studies indicate that the role of thyroidhormones in development of reproductive structureand function is similar in humans and rodents ofbothsexes.

Additionally,

alterations

in

thyroid

status

in

humans and rats during pregnancy also appear tobesimilar. T3 appears to play a significant role in malereproductivetractdevelopment inrodentsandhumans.Comparatively, T3 plays a significant role in femalereproductive tract development in rats, but not inhumans. Despite the general similarities in the role ofT3onreproductionandreproductivetractdevelopment,the exact roles of these hormones (e.g., mechanisms ofaction and interactions with other hormones) have not

been fullyevaluated and thus arenot addressed in thisstudy.

Furthermore, physiological differences in variousstages of development may produce significant differ-ences in theroleofT3 indevelopmentof thereproduc-tive

tract.

For

example,

maximal

Sertoli

cell

proliferation

occurs from late gestation through postnatal day 12 inrodents.Inhumans,itoccursfrommidgestationthrough1 year of age and from about 10 years of age throughpuberty(Sharpeetal.,2003).Suchdifferencesare likelyto translate into species differences in the outcomes ofexposurestothyroidtoxicants.

ThyroidHormoneDysfunctionHyper andhypothyroidisminducedalterationsinthe

endocrine system are seen in adult male laboratoryanimalsandhumans.However,thespecificchangesandthedirectionsofthechangesdependonthespeciesandthe thyroid dysfunction observed. Hypothyroidismproduces differing effects in juvenile male laboratoryanimals and humans. Prepubertal hypothyroidism isassociated with precocious sexual development in hu-mansandarrestofsexualmaturityinrats.

Hypothyroidism in adult female humans and rats isassociated with altered estrous cycles and interferencewith gestation, usually during the first trimester (hu-mans) or firsthalf (rodents) of pregnancy. Increasedstillbirths and abortions are noted in humans andincreasedresorptions,reducedlittersizes,andincreasedstill births are noted in rodents. This suggests thatthyroid function is necessary to maintain pregnancy inrats and humans. Hyperthyroidism in adult female

humans and rats is associated with altered levels ofLH. Alteration in sex steroid metabolism and increasedincidencesofoliogomenorrheaandamenorrheaalsoarenoted inhumans.

Fetal hypothyroidism in female rats alters reproduc-tivetractdevelopment,butasimilareffectisnotseeninthefemalehumans.Hypothyroidismintheprepubertalperiod is associated with delayed sexual maturity infemaleratsandhumans.However,therehavebeensomeobservations of precocious puberty associated withhypothyroidisminfemalehumans.

Studies of hyperthyroidism in prepubertal femalehumans and rats have produced conflicting results.Some studies indicate hyperthyroidism in humans andrats leads to early onset of menses and puberty, whileotherstudies indicate that it eitherdelays (rats) ordoesnotaffecttheonsetofmenses(humans).

CONCLUSIONSThe thyroid system is highly conserved in laboratory

rodents and humans. Thyroid dysfunctions are asso-ciatedwithnumerousmorphological,physiological,and

behavioraldisorders, includingreproductiveanddevel-opmentaldisordersinhumansandlaboratoryanimals.Despite many similarities in the thyroid systems of

humans and laboratory animals, there are significantdifferences that should be taken into account whendesigning, conducting, and interpreting animal studies.Thematerialreviewedrevealsdifferencesamongspeciesandsexesthatcouldsignificantly impactthe interpreta-tionofrodentthyroidtoxicitydataintermsofpredictingeffects in humans. Species differences that need tobeconsidered include metabolic turnover rates,basal TSHlevels, sodiumiodide symporter sensitivities, windowsof susceptibility, the role of the thyroid system onreproductive tract development and function, and themagnitudes of thyroid system changes that result inadverse health effects. In addition, a greater under-standing is needed of the molecular mechanisms ofcellular T3 uptake, intracellular transport, interactionswith other hormonal systems, and the mechanismsbywhichchanges inT3leadtoadverseeffects.

Additionaldataintheseareas,frombothhumansandrodents, will provide abetter understanding of thyroidsystem similarities and differences and will reduceuncertainties in predicting the adverse health effects ofthyroidtoxicantsonhumans.

ACKNOWLEDGMENTSThe authors gratefully acknowledge Elizabeth

Edwards for her proofreading and literature searchingassistance and skills. The authors also acknowledgeKristineWitt,Dr.MichelleHooth,Dr.OffiePoratSoldin,andDr.ThomasZoellerfortheirhelpfuldiscussionsandcomments on this manuscript. Preparation of thismanuscript was supported in partby NIEHS. ContractN01ES85425withSciencesInternational,Inc.

REFERENCESAbalovichM,LevalleO,HermesR,ScagliaH,ArandaC,ZylberszteinC,

Oneto A, Aquilano D, Gutierrez S. 1999. Hypothalamic pituitarytesticular axis and seminal parameters in hyperthyroid males.Thyroid9:857563.



12/13


13/13

491THYROIDHORMONESANDREPRODUCTIVEHEALTHSavuL,VranckxR,MayaM,NunezEA.1989.Amajorthyroxinebinding

globulin(TBG)inthemouseserum:demonstrationandontogenesis.CRAcadSciParis309:131136.

Savu L, Vranckx R, RouazeRomet M, Maya M, Nunez EA, RetonJ,Flink IL. 1991. A senescence upregulated protein: the ratthyroxinebinding globulin (TBG). Biochim Biophys Acta 1097:1922.

Scanlon MF, Toft AD. 2000. Regulation of thyrotropin secretion In:BravermanLE,UtigerRD,editors.WernerandIngbars,thethyroid,8thed.Philadelphia:LippincottWilliams&Wilkins.p234253.

SchneiderG,KopachK,OhanianH,BonnefondV,MittlerJC,ErtelNH.1979.Thehypothalamicpituitarygonadalaxisduringhyperthyroid-ism intherat.Endocrinology105:674679.

Sharpe RM, McKinnell C, Kivlin C, FisherJS. 2003. Proliferation andfunctionalmaturationofSertolicells,andtheirrelevancetodisordersoftestisfunction inadulthood.Reproduction125:769784.

TanJP, Seidler FJ, Schwinn DA, Page SO, Slotkin TA. 1997. A criticalperiod for the role of thyroid hormone in development of renalalphaadrenergicreceptors.PediatrRes42:93102.

Tani Y, Mori Y, Miura Y, Okamoto H, Inagaki A, Saito H,OisoY.1994.Molecularcloningoftheratthyroxinebindingglobulin

gene and analysis of its promoter activity. Endocrinology 135:27312736.

Tsykin A, Schreiber G. 1993. Sheep thyroxinebinding globulin: cDNAsequenceandexpression.MolCellEndocrinol98:9197.

U.S.EPA.1998.Assessmentofthyroidfollicularcelltumors.Washington,DC:EPADocumentNo.DCEPA/630/R97/002.

Vansell NR, Klaassen CD. 2001. Increasedbiliary excretion of thyroxineby microsomal enzyme inducers. Toxicol Appl Pharmacol 176:187194.

Vasudevan N, Ogawa S, Pfaff D. 2002. Estrogen and thyroid hormonereceptor interactions: physiological flexibilityby molecular specifi-city.PhysiolRev82:923944.

VerslootPM,SchroderVanDerElstJP,VanDerHeideD,BoogerdL.1997.Effects of marginal iodine deficiency during pregnancy: iodineuptake by the maternal and fetal thyroid. Am J Physiol 273:E1121E1126.

Vranckx R, Savu L, Maya M, RouazeRomet M, Nunez EA 1990.Immunological quantification of rat and mouse thyroxinebindingglobulins. Ontongenesis and sexdependence of the circulatinglevels of the thyroxinebinding globulins. Acta Endocrinol 123:649656.


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